Juliá-Colonna asymmetric epoxidation in a continuously operated chemzyme membrane reactor

Article abstract of DOI:10.1055/s-2002-25352

Two novel soluble polymer-bound oligo-L-leucines 2 and 5, Which can be retained by a membrane reactor system, have been prepared and used as catalysts for the continuously operated asymmetric epoxidation of chalcone. The optimized batch reaction condition

Full text of DOI:10.1055/s-2002-25352

LETTER
707
Juliá–Colonna Asymmetric Epoxidation in a Continuously Operated
Chemzyme Membrane Reactor
J
uliá–Colonna
v
asymmetric
e
E
poxidatio
t
n
lana B. Tsogoeva,*a,c Jens Wöltinger,a Carsten Jost,b Dietmar Reichert,a Adolf Kühnle,b Hans-Peter Krimmer,a
Karlheinz Drauza
a
Degussa AG, Research, Development and Applied Technology, Business Unit Fine Chemicals, P.O. Box 1345, 63403 Hanau-Wolfgang,
Germany
b
c
Creavis GmbH, Paul-Baumann-Straße 1, 45764 Marl, Germany
Institut für Organische Chemie, Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
Fax +49(551)399660; E-mail: stsogoe@gwdg.de
Received 4 February 2002
The interest of Degussa in developing methods for asym-
metric synthesis in a chemzyme membrane reactor6 pro-
moted further investigation of the homogeneous
enantioselective epoxidation of , -unsaturated ketones.
Abstract: Two novel soluble polymer-bound oligo-L-leucines 2
and 5, which can be retained by a membrane reactor system, have
been prepared and used as catalysts for the continuously operated
asymmetric epoxidation of chalcone. The optimized batch reaction
conditions yield epoxychalcone in high enantioselectivities (up to
94%) and conversions (over 99%) after 15 minutes.
We reasoned that the preparation of polymer enlarged oli-
go(L-leucine)s which were soluble in common organic
solvents and large enough to be retained in a membrane
reactor could allow us to develop a continuously operated
asymmetric epoxidation of trans-chalcone.
Key words: enantioselective epoxidation, homogeneous catalysis,
trans-chalcone epoxides, continuously-operated CMR, oligo(L-leu-
cine)s
There are two major approaches to synthesize homoge-
neously soluble polymer-enlarged catalysts, that is using
either linear polymers or dendrimers as carriers.
Epoxides are widely used compounds in organic synthe-
sis.1 For this reason several approaches to effect enanti-
oselective epoxidation have been made.2 Among the well-
developed methods, the Juliá–Colonna epoxidation,
which utilizes chiral polyamino acids (in particular poly-
L-leucine) as heterogeneous catalysts, has emerged as the
first reliable method for the asymmetric epoxidation of
electron-deficient olefins, exhibiting exceptionally high
chiral induction for chalcone.3
We have focused our work on linear polymers, because
they demand less synthetic effort. Thus, we prepared two
types of soluble polymer enlarged oligo(L-leucine)s 2 and
5 (Scheme 1, Scheme 2). The approach to catalyst 2 in-
volved the co-polycondensation of 1 equivalent of com-
mercially available O,O-bis(2-aminoethyl)-polyethylene-
glycol 20000 1 with 16 equivalents of L-leucine-N-car-
boxyanhydride in CHCl3.7
Degussa and their partners from the University of Liver-
pool have worked intensively on the improvement of het-
erogeneous Juliá–Colonna oxidation. A noteworthy
modification includes the introduction of percarbonate in
dimethoxyethane as a cheap oxidant/solvent system for
the use in some polyamino acid-catalysed epoxidations.4
O
O
16 eq
NH2
H2N
+
O
ca. 454
HN
1
CHCl3
O
The poly-L-leucine catalyst remained insoluble under all
the reaction conditions applied. The first homogeneous
version of the Juliá–Colonna epoxidation of trans-chal-
cone was reported recently.5 However, the conversion ob-
served was only 39% after 1 hour and 80% after 24 hours
with an ee of 95–98%.
H
O
H
N
O
N
O
H
8
N
N
H
8
ca. 454
H
H
2
Since the chiral information has to be transferred from the
catalyst to the olefinic substrate, homogeneous asymmet-
ric catalysis is a more attractive method for the synthesis
of chiral epoxides. However, up to now, no process has
made the step from an academically promising method to
an application on larger scale.
Scheme 1 Synthesis of homogeneously soluble oligo(L-leucine) 2.
We found that the resulting polyethyleneglycol-supported
oligo(L-leucine) 2 can act as an efficient homogeneous
chiral catalyst in the epoxidation of trans-chalcone 6 em-
ploying the urea hydrogen peroxide addition compound as
the oxidant. The optically active epoxy ketone 7 (Table 1)
was obtained in high enantioselectivity of 94% at a con-
version over 99% after 15 minutes.
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
1437-2096,E;2002,0,05,0707,0710,ftx,en;G03102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

708
S. B. Tsogoeva et al.
LETTER
Table 1 Asymmetric Epoxidation of Chalcone 68 with Soluble
Polymers 2 and 5
The remarkable enantiomeric excesses and conversions
we observed in the batch reactions showed the potential
for the new catalysts 2 and 5 to be used as chiral inducers
in a continuously operated chemzyme membrane reactor.
The experimental set-up is depicted in Figure 1; the mem-
brane reactor itself is a magnetically stirred filtration cell
with a volume of 10 millilitres.
O
polymer,
urea-H2O2,
NaOH, THF
O
O
Ph
Ph
Ph
Ph
6
7
Polymer Mol% of
active centers
t (min)
Conver-
ee (%)b
siona (%)
in the polymer
no
2
–
60
15
30
60
60
1.8
–
32
16
25
100
> 99
> 99
83
94
89
95
97
2
5
5
92
a Determined by HPLC (RP-18).
b Determined by HPLC chiralcel-OD column.
Epoxidation of chalcone 6 was carried out at room tem-
perature employing a saturated solution of urea–H2O2 in
THF as the oxidizing agent.8 It was confirmed that epoxi-
dation does not occur in the absence of catalyst, thus dis-
missing the possibility of background reactions (Table 1).
Figure 1 Setup for continuous epoxidation reaction.
Catalyst retention was achieved by means of a nanofiltra-
tion membrane. The epoxide and unconverted chalcone
pass through the membrane whereas the polymer-en-
larged catalyst is retained in the reactor.
Another polymer selected for reacting with L-Leu-NCA
was the first homogeneous version of styrene/aminome-
thyl styrene-copolymer 4, which was synthesized by rad-
ical co-polymerisation of styrene with p-vinylbenzyl-
amine 39 (Scheme 2). Soluble (in THF, CH2Cl2) chiral co-
polymer 5 was prepared by the reaction of 1 equivalent of
aminomethyl polystyrene 4 with 6 equivalents of L-Leu-
NCA in THF.10
Thus the advantages of catalyst retention can be united
with the effectiveness of homogeneous catalysis when a
soluble polymer is used instead of heterogeneous support.
In this concept, high reaction rate and selectivity are com-
bined with simple catalyst recovery. The residence times
of product and catalyst are decoupled, reducing catalyst
costs.6
Thus, both catalysts were tested for a number of residence
times in a chemzyme membrane reactor.11 Figure 2 shows
the conversion-time-curves for these two experiments. In
the first experiment with catalyst 2, conversions of up to
86% and ee of up to 90–95% were observed until a resi-
dence time of 25 was reached (Figure 2). The addition of
freshly prepared urea–H2O2 solution after residence time
45 leads to a significant increase in conversion as well as
enantiomeric excess. The reason for the drop of enantiose-
lectivity of catalyst 2 under the reaction conditions is still
under investigation.
NH2
O
O
O
1
6 eq
37
HN
AIBN
Cyclohexane
THF
NH2
3
4
1
37
H
O
N
5
H
N
6
While the conversion of chalcone in the second experi-
ment with catalyst 5 (Figure 2) dropped significantly to
47% after 28 residence times, little loss of selectivity was
observed (still over 90% ee). The reactor was operated un-
til the concentration of active oligo(L-leucine) 2 or 5
dropped below a critical value (at residence time 50).
Since the retention of polymer 5 is comparable (and even
higher) with that of polymer 2 (Table 2), we can assume
that deactivation of catalyst 5 dominates over its leaching
through the membrane.
H
Scheme 2 Synthesis of homogeneously soluble oligo(L-leucine) 5.
5 Was used for promoting the homogeneous asymmetric
Juliá–Colonna epoxidation. We obtained epoxide 7 with
an ee of up to 97% (92% conversion after 60 min)
(Table 1).
Synlett 2002, No. 5, 707–710 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Juliá–Colonna asymmetric Epoxidation
709
References
(1) (a) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron
1983, 39, 2323. (b) Smith, J. G. Synthesis 1984, 629.
(c) Erden, I. In Comprehensive Heterocyclic Chemistry II,
Vol. 1A; Padwa, A., Ed.; Elsevier: Oxford, 1996, 97.
(d) Adger, B. M.; Barkley, J. V.; Bergeron, S. J. Chem. Soc.,
Perkin Trans. 1. 1997, 3501. (e) Lauret, C. Tetrahedron:
Asymmetry 2001, 12, 2359.
(2) (a) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.;
Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1996, 118,
491. (b) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasaki, H.;
Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 2329.
(c) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998, 39,
1599.
(3) (a) Juliá, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed.
Engl. 1980, 19, 929. (b) Juliá, S.; Guixer, J.; Masana, J.;
Rocas, J.; Colonna, S.; Annuziata, R.; Molinari, H. J. Chem.
Soc., Perkin Trans. 1 1982, 1317. (c) Colonna, S.; Molinari,
H.; Banfi, S.; Juliá, S.; Masana, J.; Alvarez, A. Tetrahedron
1983, 39, 1635. (d) Porter, M. J.; Roberts, S. M.; Skidmore,
J. Bioorg. Med. Chem. 1999, 7, 2145.
Figure 2 Conversion plots of the continuous reactions using cata-
lysts 2 and 5.
(4) Allen, J. V.; Drauz, K.-H.; Flood, R. W.; Roberts, S. M.;
Skidmore, J. Tetrahedron Lett. 1999, 40, 5417.
(5) Flood, R. W.; Geller, T. P.; Petty, S. A.; Roberts, S. M.;
Skidmore, J.; Volk, M. Org.Lett. 2001, 3, 683.
(6) Wöltinger, J.; Bommarius, A. S.; Drauz, K.; Wandrey, C.
Org. Process Res. Dev. 2001, 5, 241.
Table 2 Summary of the Two Continuous Reactions
(7) To a stirred solution of O,O-bis(2-aminoethyl)-
polyethylenglycol 20000 1 (3.05 g, 0.152 mmol, 1 equiv) in
CHCl3 (60 mL) was added a solution of L-leucine-N-
carboxyanhydride (384 mg, 2.44 mmol, 16 equiv) in CHCl3
(27 mL). The reaction mixture was stirred under nitrogen at
r.t. for 20 h. After solvent evaporation under vacuum,
addition of diethyl ether caused precipitation of a white solid
(3.3 g).
(8) Asymmetric epoxidation of trans-chalcone (batch
reaction). The following procedure is representative of
these reactions. To a stirred solution of polymer 2
(3.89 10–3 mmol; 32 mol% of active centers) in THF
(0.5 mL) was added NaOH (0.065 mmol) and chalcone
(0.024 mmol). Stirring at r.t. was continued for 20 min
before the addition, (over 15 min) of a sat. solution of
urea–H2O2 (0.213 mmol, 98% pure from Aldrich) in THF
(1.5 mL; prepared using an ultrasound bath over 45 min
followed by filtration).
(9) (a) 4-vinylbenzylamine (0.80 g, 6.08 mmol; prepared
according to the literature, see ref.9b), styrene (12.7 g, 13.9
mL; 122 mmol) and AIBN (119 mg, 0.72 mmol) were
dissolved in cyclohexane (15 mL). The solution was
degassed three times by evaporation (with stirring) and re-
pressurizing with N2, followed by heating at 50 °C for 90 h.
The reaction mixture was cooled to r.t., dropped into
methanol (600 mL), and the polymer 4 (11 g) was filtered
off. (b) Zhou, W.-J.; Kurth, M. J.; Hsieh, Y.-L.; Krochta, J.
M. Macromolecules 1999, 32, 5507.
(10) To a solution of styrene/aminomethyl styrene copolymer 4
(3.51 g, 0.88 mmol, 1 equiv) in THF (115 mL) was added a
solution of L-leucine-N-carboxyanhydride (829 mg, 5.28
mmol, 6 equiv) in THF (60 mL). The reaction mixture was
stirred under nitrogen at r.t. for 20 h, then concentrated to ca.
20 mL and dropped into methanol (400 mL); 3.5 g of
polymer was filtered off.
PEG-bound
Catalyst 2
Aminomethyl
Polystyrene-
Bound Catalyst 5
Retention of catalysta
Average conversion
Average ee
98.87%
69.3%
98.99%
80.0%
91.5%
80.6 %
a Retention was calculated by isolation of the polymer from the re-
actor after the reaction was stopped.
It is interesting to note that the epoxidation reaction in the
membrane reactor, catalyzed by polymer 5, reduces the
time required for 92–94% conversion of chalcone from 60
minutes to 30 minutes (Table 1). This reaction showed ee
of up to 90–95% throughout the 50 residence times.
The polymer catalysts 2 and 5 that have been employed in
the continuous reactions were recovered and reused for
batch asymmetric epoxidation reactions. No decrease in
ee (up to 97%) and conversion (around 85% after 60 min)
was observed.
In conclusion, we have prepared two novel polymer-sup-
ported oligo(L-leucine)s that are soluble in organic sol-
vents and we have effected the first enantioselective
synthesis of epoxy chalcone in a continuously-operated
chemzyme membrane reactor. It is shown that the catalyst
retention in the reactor solves catalyst recovery problems
and provides a simple reaction procedure associated with
high catalyst activity and selectivity.
(11) (a) Continuous epoxidation of trans-chalcone using
catalyst 2. The nanofiltration membrane (MPF-50 of Koch
Membrane Systems, Düsseldorf, Germany. The cutoff is
defined by a substance with a certain molecular weight,
leading to 99.8% retention) was placed in a 10 mL
Acknowledgement
Dedicated to Professor Dr. Dr. h.c. L. F. Tietze on the occasion of
his 60th birthday.
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S. B. Tsogoeva et al.
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chemzyme membrane reactor (CMR), and THF was
NaOH (0.052 mol) at r.t. for 30 min and then filtered) was
pumped in the reactor (13 mL/h) using another Pharmacia P-
500 pump. The product and unconverted chalcone were
collected in a fraction collector (Pharmacia Frac 100) with a
residence time of 30 min. (b) Continuous epoxidation of
trans-chalcone using catalyst 5. The same equipment and
conditions were used as described above. The following
concentration of polymer 5 was used: 0.190 mmol of active
centers.
transported through the reactor (20 mL/h). The mixture of
polymer catalyst 2 (0.089 mmol of active centers), dissolved
in of THF (6 mL), and NaOH (0.775 mmol) was stirred at r.t.
for 20 min. The solution was filtered, and the filtrate was
pumped into the membrane reactor using a Pharmacia P-500
pump. Afterwards, a sat. solution of urea–H2O2 (1.4 10–4
mol/L) was pumped through the membrane reactor with a
flow rate of 7 mL/h. At the same time a solution of chalcone
(48 mmol/L in THF) (which was previously stirred with
Synlett 2002, No. 5, 707–710 ISSN 0936-5214 © Thieme Stuttgart · New York